Project Summary/Abstract Biliary atresia (BA) and the other childhood cholestatic liver diseases are significant causes of chronic liver disease in children, and the leading causes for liver transplantation in pediatrics. The initial funding periods leading to the current Childhood Liver Disease Research Network (ChiLDReN) have resulted in unprecedented collections of well phenotyped subjects and banked data and biological specimens. Although ongoing recruitment of subjects with these rare conditions is needed to allow full attainment of many of the individual study Aims, the collection of subjects, data, and biospecimens is now sufficient to support meaningful investigation into the pathogenesis of these diseases and allow thorough genomic screens to elucidate etiologies and modifiers of disease phenotypes. This next funding period will allow completion of the ongoing studies and add study of primary sclerosing cholangitis. Furthermore, in conjunction with completing the ongoing studies, such as PUSH, identification of predictors of liver disease development will be possible via the approved ancillary trial of non-invasive markers of disease (led by Dr. Murray). The Seattle Clinical Center (CC) has the experience, expertise, and proven track record to continue participation in ChiLDReN, and has the expected patients over time to support the ongoing and new consortium trials. Dr. Murray and her CC team has additionally proposed a Pilot and Feasibility Trial to study the impact of parenteral nutrition, with standard intralipids versus Omegaven, on malnourished children with end-stage liver disease due to BA. This study has the potential to change the standard of care for these vulnerable patients, improve their outcomes, and enhance our understanding of the pathogenesis of this obliterative cholangiopathy. Furthermore, to better understand the etiology of BA and potentially identify unique underlying candidate genes, Dr. Murray also proposes to perform whole genome sequencing and rare-variant analysis on a subset of the ChiLDReN BA trios to identify variants of both large and small effects in families with BA and ductal plate configuration.